This application is a response to the Request for Application (RFA) entitled: Prenatal Alcohol Exposure Among High-Risk Populations: Relationship to Sudden Infant Death Syndrome (SIDS) (RFA: HD-03-004). Our group is applying for the award of the Developmental Biology and Pathology Center. As requested in the RFA, we plan to conduct basic and applied research related to molecular and biological aspects of alcohol related injury to the brain, systemic organs, and placenta in the subject population. We hypothesize that prenatal exposure to alcohol adversely affects the development of the serotonergic (5-HT) system in the medulla oblongata of the brainstem, and thereby puts the vulnerable fetus/infant at risk for sudden death by compromising an array of homeostatic reflexes which are all influenced by the medullary 5-HT neurons, and which protect the fetus/infant from life-threatening stressors, e.g., hypoxia, hypercarbia, and hypotension. This hypothesis is a direct outgrowth of our brainstem analysis in two independent databases of SIDS and control cases, including in the Northern Plains Indians, a high-risk population. We propose 5 Specific Aims for the sample study to examine inter-relationships between brainstem 5-HT and vasoactive intestinal peptide (VIP), the latter shown to play a pivotal role in the pathogenesis of alcohol-induced injury in animal models. In Specific Aim 1 we will determine if abnormalities in the medullary 5-HT system correlate with VIP abnormalities in this system in fetuses and/or infants with sudden death who were exposed to prenatal alcohol. In Specific Aim 2, we will determine if markers of oxidative stress correlate with5-HT-related abnormalities in the medullary 5-HT system in such fetuses/infants. In Specific Aim 3, we address the question if the same brainstem abnormalities reported by us in SIDS infants are present in unexplained stillbirth, data which would substantiate the idea that there is a continuum of disease-effect from the fetal period through infancy. In Specific Aim 4, we seek to know if polymorphisms or mutations in 5-HT-related markers are associated with medullary 5-HT system abnormalities and an increased risk for sudden death in fetuses/infants exposed to prenatal alcohol. In Specific Aim 5, we address issues related to VIP expression in the placenta, the key organ of maternal-fetal homeostasis, based upon reports of alcohol-induced reductions in placental VIP in animal models. These human studies should help provide the necessary critical steps to translate basic science findings into therapeutic strategies for the prevention or amelioration of prenatal alcohol-induced injury to the developing human brain.